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FOXA1

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FOXA1
Identifiers
AliasesFOXA1, HNF3A, TCF3A, forkhead box A1
External IDsOMIM: 602294; MGI: 1347472; HomoloGene: 3307; GeneCards: FOXA1; OMA:FOXA1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3169

15375

Ensembl

ENSG00000129514

ENSMUSG00000035451

UniProt

P55317

P35582

RefSeq (mRNA)

NM_004496

NM_008259

RefSeq (protein)

NP_004487

NP_032285

Location (UCSC)Chr 14: 37.59 – 37.6 MbChr 12: 57.59 – 57.59 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Forkhead box protein A1 (FOXA1), also known as hepatocyte nuclear factor 3-alpha (HNF-3A), is a protein that in humans is encoded by the FOXA1 gene.[5][6][7]

Function

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FOXA1 is a pioneer factor, a transcription factor that directly binds condensed chromatin, facilitating the binding of other transcription factors.[8] In prostate cells, FOXA1 interacts with the androgen receptor (AR) to drive transcription of prostate-specific genes.[8]

FOXA1 is a member of the forkhead class of DNA-binding proteins. Similar family members in mice have roles in the regulation of metabolism and in the differentiation of the pancreas and liver.[5]

Structure

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FOXA1 is a member of the forkhead domain transcription factor family. The forkhead domain is essential for its DNA-binding function, and consists of three alpha helices, three beta strands, and two loops (called "wings"). The domain binds along the DNA major groove and the wings directly contact the DNA.[9]

FOXA1 is modified by the O-GlcNAc post-translational modification.[10]

Marker in breast cancer

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FOXA1 in breast cancer is highly correlated with ERα+, GATA3+, and PR+ protein expression as well as endocrine signaling. FOXA1 acts as a pioneer factor for ERa in ERα+ breast cancer, and its expression might identify ERα+ cancers that undergo rapid reprogramming of ERa signaling that is associated with poor outcomes and treatment resistance.[11] Conversely, in ERα− breast cancer FOXA1 is highly correlated with low-grade morphology and improved disease free survival. FOXA1 is a downstream target of GATA3 in the mammary gland.[12] Expression in ERα− cancers may identify a subset of tumors that is responsive to other endocrine therapies such as androgen receptor antagonist treatment.[13][14]

Role in cancer

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FOXA1 is one of the most frequently altered genes in prostate cancer, with mutations in the coding sequence of up to 9% of localized prostate cancer cases, and 13% of metastatic treatment-resistant prostate cancers.[8] Most cancer-associated FOXA1 mutations are missense mutations, changing the amino acid sequence of the fork head domain's DNA-binding sites.[8]

Expression of FOXA1 correlates with two EMT markers, namely Twist1 and E-cadherin in breast cancer.[15]

Chemical probe development

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Being a transcription factor lacking structurally ordered small molecule-binding sites, FOXA1 has generally been considered to be an undruggable protein. Using a chemical proteomics approach directed against cysteines, researchers from Scripps Research identified a tryptoline acrylamide chemical probe WX-02-23 that reacts with FOXA1 C258 site-specifically and stereospecifically. WX-02-23 binds FOXA1 in a DNA-dependent manner, and WX-02-23 likewise enhances FOXA1 interaction with DNA.[16]

Chemical structure of WX-02-23.[17]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000129514 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000035451 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: forkhead box A1".
  6. ^ Bingle CD, Gowan S (June 1996). "Molecular cloning of the forkhead transcription factor HNF-3 alpha from a human pulmonary adenocarcinoma cell line". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1307 (1): 17–20. doi:10.1016/0167-4781(96)00058-9. PMID 8652662.
  7. ^ Mincheva A, Lichter P, Schütz G, Kaestner KH (February 1997). "Assignment of the human genes for hepatocyte nuclear factor 3-alpha, -beta, and -gamma (HNF3A, HNF3B, HNF3G) to 14q12-q13, 20p11, and 19q13.2-q13.4". Genomics. 39 (3): 417–419. doi:10.1006/geno.1996.4477. PMID 9119385.
  8. ^ a b c d Teng M, Zhou S, Cai C, Lupien M, He HH (January 2021). "Pioneer of prostate cancer: past, present and the future of FOXA1". Protein Cell. 12 (1): 29–38. doi:10.1007/s13238-020-00786-8. PMC 7815845. PMID 32946061.
  9. ^ Martin EM, Orlando KA, Yokobori K, Wade PA (December 2021). "The estrogen receptor/GATA3/FOXA1 transcriptional network: lessons learned from breast cancer". Curr Opin Struct Biol. 71: 65–70. doi:10.1016/j.sbi.2021.05.015. PMC 8648900. PMID 34225008.
  10. ^ Liu, Yajie; Yu, Kairan; Kong, Xiaotian; Zhang, Keren; Wang, Lingyan; Zhang, Nana; Chen, Qiushi; Niu, Mingshan; Li, Wenli; Zhong, Xiaomin; Wu, Sijin; Zhang, Jianing; Liu, Yubo (2023-08-18). "FOXA1 O-GlcNAcylation–mediated transcriptional switch governs metastasis capacity in breast cancer". Science Advances. 9 (33): eadg7112. Bibcode:2023SciA....9G7112L. doi:10.1126/sciadv.adg7112. ISSN 2375-2548. PMC 10438466. PMID 37595040.
  11. ^ Ross-Innes CS, Stark R, Teschendorff AE, Holmes KA, Ali HR, Dunning MJ, et al. (January 2012). "Differential oestrogen receptor binding is associated with clinical outcome in breast cancer". Nature. 481 (7381): 389–393. Bibcode:2012Natur.481..389R. doi:10.1038/nature10730. PMC 3272464. PMID 22217937.
  12. ^ Kouros-Mehr H, Slorach EM, Sternlicht MD, Werb Z (December 2006). "GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland". Cell. 127 (5): 1041–1055. doi:10.1016/j.cell.2006.09.048. PMC 2646406. PMID 17129787.
  13. ^ Albergaria A, Paredes J, Sousa B, Milanezi F, Carneiro V, Bastos J, et al. (2009). "Expression of FOXA1 and GATA-3 in breast cancer: the prognostic significance in hormone receptor-negative tumours". Breast Cancer Research. 11 (3): R40. doi:10.1186/bcr2327. PMC 2716509. PMID 19549328.
  14. ^ Sanga S, Broom BM, Cristini V, Edgerton ME (September 2009). "Gene expression meta-analysis supports existence of molecular apocrine breast cancer with a role for androgen receptor and implies interactions with ErbB family". BMC Medical Genomics. 2: 59. doi:10.1186/1755-8794-2-59. PMC 2753593. PMID 19747394.
  15. ^ BenAyed-Guerfali D, Dabbèche-Bouricha E, Ayadi W, Trifa F, Charfi S, Khabir A, et al. (June 2019). "Association of FOXA1 and EMT markers (Twist1 and E-cadherin) in breast cancer". Molecular Biology Reports. 46 (3): 3247–3255. doi:10.1007/s11033-019-04784-w. PMID 30941644. S2CID 91190545.
  16. ^ Won, Sang Joon; Zhang, Yuxiang; Reinhardt, Christopher J.; Hargis, Lauren M.; MacRae, Nicole S.; DeMeester, Kristen E.; Njomen, Evert; Remsberg, Jarrett R.; Melillo, Bruno; Cravatt, Benjamin F.; Erb, Michael A. (November 2024). "Redirecting the pioneering function of FOXA1 with covalent small molecules". Molecular Cell. 84 (21): 4125–4141.e10. doi:10.1016/j.molcel.2024.09.024. PMID 39413792.
  17. ^ Won, Sang Joon; Zhang, Yuxiang; Reinhardt, Christopher J.; Hargis, Lauren M.; MacRae, Nicole S.; DeMeester, Kristen E.; Njomen, Evert; Remsberg, Jarrett R.; Melillo, Bruno; Cravatt, Benjamin F.; Erb, Michael A. (November 2024). "Redirecting the pioneering function of FOXA1 with covalent small molecules". Molecular Cell. 84 (21): 4125–4141.e10. doi:10.1016/j.molcel.2024.09.024. PMID 39413792.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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